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1.  A budesonide prodrug accelerates treatment of colitis in rats. 
Gut  1994;35(10):1439-1446.
Although oral glucocorticoids are the treatment of choice for moderate to severe ulcerative pancolitis, their systemic side effects and adrenal suppression account for considerable morbidity. An oral glucocorticoid-conjugate (prodrug), budesonide-beta-D-glucuronide, which is not absorbed in the small intestine but is hydrolysed by colonic bacterial and mucosal beta-glucuronidase to release free budesonide into the colon was synthesised. The objective of this study was to compare treatment with budesonide-beta-D-glucuronide with treatment with free budesonide by examining: (1) the healing of experimental colitis and (2) the extent of adrenal suppression. Pancolitis was induced with 4% acetic acid. Animals were then randomised to receive oral therapy for 72 hours with (1) budesonide-beta-D-glucuronide, (2) free budesonide, or (3) vehicle. Drug efficacy and colitic healing was determined by measuring gross colonic ulceration, myeloperoxidase activity, and in vivo colonic fluid absorption. Adrenal suppression was determined by measuring plasma adrenocorticotrophic hormone and serum corticosterone. Vehicle-treated colitis animals had gross ulceration, increased myeloperoxidase activity, and net colonic fluid secretion. Treatment with oral budesonide-beta-D-glucuronide accelerated all measures of colitis healing at a fourfold lower dose than did free budesonide. Furthermore, treatment with budesonide-beta-D-glucuronide did not result in adrenal suppression whereas free budesonide treatment did. A newly synthesised orally administered glucocorticoid-conjugate accelerates colitis healing with limited adrenal suppression. Development of an orally administered colon-specific steroid delivery system represents a novel approach to inflammatory bowel disease treatment.
PMCID: PMC1375021  PMID: 7959202
2.  Development and Evaluation of a Novel Pellet-Based Tablet System for Potential Colon Delivery of Budesonide 
Journal of Drug Delivery  2012;2012:905191.
Budesonide, a potent glucocorticoid, is used for the treatment of inflammatory bowel diseases. Current available oral formulations of budesonide have low efficacy against ulcerative colitis because of the premature drug release in the upper part of the gastrointestinal tract. In this paper a pH- and time-controlled colon-targeted pellet-based tablet of budesonide was established. Pellet cores were prepared by extrusion-spheronization method and further coated with xanthan gum (barrier layer), Eudragit NE30D and L30D55 combination (inner layer), and Eudragit FS30 (as enteric layer) sequentially to achieve the required release profile. The coated pellets then compressed into tablets using inert tabletting granules of Cellactose or Pearlitol. Release studies, performed in simulated gastric, intestinal, and colon pH were used in sequence to mimic the gastrointestinal transit. The influence of formulation variables like barrier layer thickness, inner layer composition, and enteric coat thickness on drug release were investigated and the coated pellets that contained 12% weight gain in xanthan gum layer, Eudragit L30D55 and Eudragit NE30D with a ratio of 3 : 7 in inner layer with 30% weight gain and 25% weight gain in Eudragit FS layer were found to protect the drug release in stomach and small intestine and 83.35 ± 2.4 of budesonide was released at 24 h. The drug release from the tablets prepared using 40% Cellactose 80 as tableting excipient was found to be closely similar to that of uncompressed pellets.
PMCID: PMC3346988  PMID: 22577558
3.  Therapeutic benefits of budesonide in gastroenterology 
Budesonide is a synthetic steroid of the glucocorticoid family with a high topical anti-inflammatory activity. Enteric-coated formulations resist gastric-acid degradation, delivering active drug to the small intestine and proximal colon. Budesonide has a high first-pass metabolism with minimal systemic absorption. It is therefore felt to cause fewer side effects than traditional glucocorticosteroids and to be generally well tolerated. The aim of this paper is to examine the utility of this medication in frequently encountered gastrointestinal conditions: Crohn's disease, ulcerative colitis, microscopic colitis and eosinophilic oesophagitis. A Medline search was performed to find published original research and review articles relating to the use budesonide in common gastroenterological conditions. The results showed that budesonide is efficacious in the induction and short-term maintenance of Crohn's disease. Budesonide is the best-documented treatment for microscopic colitis. It is well proven to be effective in the induction of remission in collagenous colitis but its use in lymphocytic colitis remains less well documented. In conclusion, budesonide is an effective glucocorticosteroid therapy for many chronic gastrointestinal diseases. In combination with its efficacy, the low incidence of serious side effects associated with this drug should keep it at the forefront in the therapeutic arsenal of any gastroenterologist.
PMCID: PMC3513866  PMID: 23251737
budesonide; Crohn's disease; eosinophilic oesophagitis; microscopic colitis; pouchitis; ulcerative colitis
4.  Effect of differing doses of inhaled budesonide on markers of airway inflammation in patients with mild asthma 
Thorax  1999;54(2):108-114.
BACKGROUND—It is desirable to prescribe the minimal effective dose of inhaled steroids to control asthma. To ensure that inflammation is suppressed whilst using the lowest possible dose, a sensitive and specific method for assessing airway inflammation is needed.
METHODS—The usefulness of exhaled nitric oxide (NO), sputum eosinophils, and methacholine airway responsiveness (PC20) for monitoring airway inflammatory changes following four weeks of treatment with an inhaled corticosteroid (budesonide via Turbohaler) were compared. Mild stable steroid naive asthmatic subjects were randomised into two double blind, placebo controlled studies. The first was a parallel group study involving three groups receiving either 100 µg/day budesonide (n = 8), 400 µg/day budesonide (n = 7), or a matched placebo (n = 6). The second was a crossover study involving 10 subjects randomised to receive 1600 µg budesonide or placebo. The groups were matched with respect to age, PC20, baseline FEV1 (% predicted), exhaled NO, and sputum eosinophilia.
RESULTS—There were significant improvements in FEV1 following 400 µg and 1600 µg budesonide (11.3% and 6.5%, respectively, p<0.05). This was accompanied by significant reductions in eosinophil numbers in induced sputum (0.7 and 0.9 fold, p<0.05). However, levels of exhaled NO were reduced following each budesonide dose while PC20 was improved only with 1600 µg budesonide. These results suggest that exhaled NO and PC20 may not reflect the control of airway inflammation as accurately as the number of eosinophils in sputum. There were dose dependent changes in exhaled NO, sputum eosinophils, and PC20 to inhaled budesonide but a plateau response of exhaled NO was found at a dose of 400 µg daily.
CONCLUSION—Monitoring the number of eosinophils in induced sputum may be the most accurate guide to establish the minimum dose of inhaled steroids needed to control inflammation. This, however, requires further studies involving a larger number of patients.

PMCID: PMC1745406  PMID: 10325913
5.  Eosinophilia in a patient with cyclical vomiting: a case report 
Eosinophilic gastritis is related to eosinophilic gastroenteritis, varying only in regards to the extent of disease and small bowel involvement. Common symptoms reported are similar to our patient's including: abdominal pain, epigastric pain, anorexia, bloating, weight loss, diarrhea, ankle edema, dysphagia, melaena and postprandial nausea and vomiting. Microscopic features of eosinophilic infiltration usually occur in the lamina propria or submucosa with perivascular aggregates. The disease is likely mediated by eosinophils activated by various cytokines and chemokines. Therapy centers around the use of immunosuppressive agents and dietary therapy if food allergy is a factor.
Case presentation
The patient is a 31 year old Caucasian female with a past medical history significant for ulcerative colitis. She presented with recurrent bouts of vomiting, abdominal pain and chest discomfort of 11 months duration. The bouts of vomiting had been reoccurring every 7–10 days, with each episode lasting for 1–3 days. This was associated with extreme weakness and cachexia. Gastric biopsies revealed intense eosinophilic infiltration. The patient responded to glucocorticoids and azathioprine. The differential diagnosis and molecular pathogenesis of eosinophilic gastritis as well as the molecular effects of glucocorticoids in eosinophilic disorders are discussed.
The patient responded to a combination of glucocorticosteroids and azathioprine with decreased eosinophilia and symptoms. It is likely that eosinophil-active cytokines such as interleukin-3 (IL-3), granulocyte macrophage colony stimulating factor (GM-CSF) and IL-5 play pivotal roles in this disease. Chemokines such as eotaxin may be involved in eosinophil recruitment. These mediators are downregulated or inhibited by the use of immunosuppressive medications.
PMCID: PMC425596  PMID: 15144561
6.  Combination formoterol and inhaled steroid versus beta2-agonist as relief medication for chronic asthma in adults and children 
Formoterol has a fast onset of action and can therefore be used to relieve symptoms of asthma. A combination inhaler can deliver formoterol with different doses of inhaled corticosteroid; when used as a reliever both drugs will be delivered more frequently when asthma symptoms increase. This has the potential to treat both bronchoconstriction and inflammation in the early stages of exacerbations.
To assess the efficacy and safety of combined inhalers containing both formoterol and an inhaled corticosteroid when used for reliever therapy in adults and children with chronic asthma.
Search methods
We last searched the Cochrane Airways Group trials register in April 2009, and no new studies were found for inclusion in the review.
Selection criteria
Randomised trials in adults and children with chronic asthma, where a combination inhaler containing formoterol and inhaled corticosteroid is compared with fast-acting beta2-agonist alone for the relief of asthma symptoms. This should be the only planned difference between the trial arms.
Data collection and analysis
Two review authors independently extracted the characteristics and results of each study. Authors or manufacturers were asked to supply unpublished data in relation to primary outcomes.
Main results
Three trials involving 5905 participants were included. In patients with mild asthma who do not need maintenance treatment, no clinically important advantages of budesonide/formoterol as reliever were found in comparison to formoterol as reliever.
Two studies enrolled patients with more severe asthma who were not controlled on high doses of inhaled corticosteroids (around 700 mcg/day in adults), and had suffered a clinically important asthma exacerbation in the past year. Hospitalisations related to asthma in the two studies comparing budesonide/formoterol for maintenance and relief with the same dose of budesonide/formoterol for maintenance with terbutaline for relief yielded an odds ratio of 0.68 (95% CI 0.40 to 1.16), which was not a statistically significant reduction. In adults there was a reduction in exacerbations requiring oral corticosteroids compared to terbutaline, odds ratio 0.54 (95% CI 0.44 to 0.65), which translates into a number needed to treat over 12 months of 15 (95% CI 13 to 21). The study in children found less serious adverse events with budesonide/formoterol used for maintenance and relief. There was no significant difference in annual growth in children using budesonide/formoterol reliever in comparison to terbutaline.
Authors’ conclusions
In mild asthma it is not yet known whether patients who use a budesonide/formoterol inhaler for relief of asthma symptoms derive any clinically important benefits. In more severe asthma, two studies enrolled patients who were not controlled on inhaled corticosteroids, and had suffered an exacerbation in the previous year, and then had their maintenance inhaled corticosteroids reduced in both arms of the study. Under these conditions the studies demonstrated a reduction in the risk of exacerbations that require oral corticosteroids with budesonide/formoterol for maintenance and relief in comparison with budesonide/formoterol for maintenance and terbutaline or formoterol for relief. The incidence of serious adverse events in children was also less using budesonide/formoterol for maintenance and relief in one study, which similarly enrolled children who were not controlled on inhaled corticosteroids, and who had their maintenance inhaled corticosteroids reduced at the start of the study. This study also compared an explorative maintenance dose of budesonide/formoterol that is not approved for treatment.
PMCID: PMC4023854  PMID: 19160317
Administration, Inhalation; Anti-Asthmatic Agents [*administration & dosage]; Asthma [*drug therapy]; Bronchial Diseases [drug therapy]; Bronchodilator Agents [*administration & dosage]; Budesonide [*administration & dosage]; Chronic Disease; Constriction, Pathologic [drug therapy]; Drug Combinations; Ethanolamines [*administration & dosage]; Randomized Controlled Trials as Topic; Terbutaline [administration & dosage]; Adolescent; Adult; Child; Humans
7.  Long-term safety and efficacy of budesonide in the treatment of ulcerative colitis 
Ulcerative colitis (UC) is a chronic, relapsing, and remitting inflammatory disease involving the large intestine (colon). Treatment seeks to break recurrent inflammation episodes by inducing and maintaining remission. Historically, oral systemic corticosteroids played an important role in inducing remission of this chronic disease; however, their long-term use is limited and can lead to adverse events. Budesonide is a synthetic steroid with potent local anti-inflammatory effects and low systemic bioavailability due to high first-pass hepatic metabolism. Several studies have demonstrated oral budesonide’s usefulness in treating active mild to moderate ileocecal Crohn’s disease and microscopic colitis and in an enema formulation for left sided UC. However, there is limited information regarding oral budesonide’s efficacy in UC. A novel oral budesonide formulation using a multimatrix system (budesonide-MMX) to extend drug release throughout the colon has been developed recently and seems to be an effective treatment in active left sided UC patients. This article summarizes budesonide’s long-term safety and efficacy in treating UC.
PMCID: PMC3921089  PMID: 24523594
budesonide; ulcerative colitis; Crohn’s disease; safety
8.  A retrospective database study comparing treatment outcomes and cost associated with choice of fixed-dose inhaled corticosteroid/long-acting β2-agonists for asthma maintenance treatment in Germany 
This retrospective, observational cohort study aimed to compare treatment outcomes and healthcare costs in the year after initiation of maintenance treatment with budesonide/formoterol or salmeterol/fluticasone in a German healthcare setting.
Data on German asthma patients initiating treatment with budesonide/formoterol or salmeterol/fluticasone between June 2001 and June 2005 were obtained from the IMS Disease Analyzer database. The primary outcome was the probability of treatment success, defined according to short-acting β2-agonist prescriptions and switches or addition of controller medications, during the postindex year. A secondary definition of treatment success included hospitalisations and oral corticosteroid (OCS) prescriptions. Secondary outcomes included severe asthma exacerbations, defined as ≥1 OCS prescription, asthma-related hospitalisation and/or referral. The effect of treatment on costs was estimated using generalised linear models, adjusting for patient and physician characteristics.
There were no significant differences between the budesonide/formoterol (n=1456) and salmeterol/fluticasone (n=982) groups in disease severity markers in the pre-index year. Patients on budesonide/formoterol had a 44% greater probability of treatment success [odds ratio (OR): 1.44; p = 0.0003] according to the primary definition and a 26% greater probability (OR: 1.26; p = 0.0119) according to the secondary definition, fewer severe exacerbations (−33.4%; p = 0.0123) and fewer OCS prescriptions (−31.5%; p = 0.0082) compared with salmeterol/fluticasone, after controlling for baseline characteristics. Adjusting for covariates, budesonide/formoterol had a significant inverse relationship on asthma-related costs compared with salmeterol/fluticasone (−13.4%; p < 0.001). Total cost (asthma- and non-asthma-related costs) was 12.6% lower for budesonide/formoterol (p < 0.0001).
This study suggests that for patients with chronic asthma in Germany, budesonide/formoterol rather than salmeterol/fluticasone had a higher likelihood of treatment success, and that budesonide/formoterol is the less costly option. Although the cohorts appeared to be well matched at baseline, the results should be interpreted with caution given the observational nature of the study.
PMCID: PMC2680329  PMID: 18803555
9.  Fecal microbiota transplantation and prednisone for severe eosinophilic gastroenteritis 
World Journal of Gastroenterology : WJG  2014;20(43):16368-16371.
Eosinophilic gastroenteritis is a rare disease of unknown etiology. It is characterized by patchy or diffuse eosinophilic infiltration of the bowel wall to a variable depth and various gastrointestinal manifestations. We describe a case of severe eosinophilic gastroenteritis presenting as frequent bowel obstruction and diarrhea in a 35-year-old man. The patient was misdiagnosed and underwent surgery because of intestinal obstruction when he was first admitted to a local hospital. Then he was misdiagnosed as having Crohn’s disease in another university teaching hospital. Finally, the patient asked for further treatment from our hospital because of the on-going clinical trial for treating refractory Crohn’s disease by fecal microbiota transplantation. Physical examination revealed a slight distended abdomen with diffuse tenderness. Laboratory investigation showed the total number of normal leukocytes with neutrophilia as 90.5%, as well as eosinopenia, monocytopenia and lymphocytopenia. Barium radiography and sigmoidoscopy confirmed inflammatory stenosis of the sigmoid colon. We diagnosed the patient as having eosinophilic gastroenteritis by multi-examinations. The patient was treated by fecal microbiota transplantation combined with oral prednisone, and was free from gastrointestinal symptoms at the time when we reported his disease. This case highlights the importance of awareness of manifestations of a rare disease like eosinophilic gastroenteritis.
PMCID: PMC4239532  PMID: 25473198
Eosinophilic gastroenteritis; Bowel obstruction; Diarrhea; Fecal microbiota transplantation; Prednisone
10.  Randomised controlled trial of montelukast plus inhaled budesonide versus double dose inhaled budesonide in adult patients with asthma 
Thorax  2003;58(3):211-216.
Background: Inhaled corticosteroids (ICS) affect many inflammatory pathways in asthma but have little impact on cysteinyl leukotrienes. This may partly explain persistent airway inflammation during chronic ICS treatment and failure to achieve adequate asthma control in some patients. This double blind, randomised, parallel group, non-inferiority, multicentre 16 week study compared the clinical benefits of adding montelukast to budesonide with doubling the budesonide dose in adults with asthma.
Methods: After a 1 month single blind run in period, patients inadequately controlled on inhaled budesonide (800 µg/day) were randomised to receive montelukast 10 mg + inhaled budesonide 800 µg/day (n=448) or budesonide 1600 µg/day (n=441) for 12 weeks.
Results: Both groups showed progressive improvement in several measures of asthma control compared with baseline. Mean morning peak expiratory flow (AM PEF) improved similarly in the last 10 weeks of treatment compared with baseline in both the montelukast + budesonide group and in the double dose budesonide group (33.5 v 30.1 l/min). During days 1–3 after start of treatment, the change in AM PEF from baseline was significantly greater in the montelukast + budesonide group than in the double dose budesonide group (20.1 v 9.6 l/min, p<0.001), indicating faster onset of action in the montelukast group. Both groups showed similar improvements with respect to "as needed" ß agonist use, mean daytime symptom score, nocturnal awakenings, exacerbations, asthma free days, peripheral eosinophil counts, and asthma specific quality of life. Both montelukast + budesonide and double dose budesonide were generally well tolerated.
Conclusion: The addition of montelukast to inhaled budesonide is an effective and well tolerated alternative to doubling the dose of inhaled budesonide in adult asthma patients experiencing symptoms and inadequate control on budesonide alone.
PMCID: PMC1746596  PMID: 12612295
11.  Early phase resolution of mucosal eosinophilic inflammation in allergic rhinitis 
Respiratory Research  2010;11(1):54.
It is widely assumed that apoptosis of eosinophils is a central component of resolution of allergic airway disease. However, this has not been demonstrated in human allergic airways in vivo. Based on animal in vivo observations we hypothesised that steroid-induced resolution of human airway eosinophilic inflammation involves inhibition of CCL5 (RANTES), a CC-chemokine regulating eosinophil and lymphocyte traffic, and elimination of eosinophils without evident occurrence of apoptotic eosinophils in the diseased tissue.
To determine mucosal eosinophilia, apoptotic eosinophils, general cell apoptosis and cell proliferation, and expression of CCL5 and CCL11 (eotaxin) in human allergic airway tissues in vivo at resolution of established symptomatic eosinophilic inflammation.
Twenty-one patients with intermittent (birch and/or grass) allergic rhinitis received daily nasal allergen challenges for two seven days' periods separated by more than two weeks washout. Five days into these "artificial pollen seasons", nasal treatment with budesonide was instituted and continued for six days in a double blinded, randomized, placebo-controlled, and crossover design. This report is a parallel group comparison of nasal biopsy histochemistry data obtained on the final day of the second treatment period.
Treatments were instituted when clinical rhinitis symptoms had been established. Compared to placebo, budesonide reduced tissue eosinophilia, and subepithelial more than epithelial eosinophilia. Steroid treatment also attenuated tissue expression of CCL5, but CCL11 was not reduced. General tissue cell apoptosis and epithelial cell proliferation were reduced by budesonide. However, apoptotic eosinophils were not detected in any biopsies, irrespective of treatment.
Inhibition of CCL5-dependent recruitment of cells to diseased airway tissue, and reduced cell proliferation, reduced general cell apoptosis, but not increased eosinophil apoptosis, are involved in early phase steroid-induced resolution of human allergic rhinitis.
PMCID: PMC2873933  PMID: 20459697
12.  Eosinophils in the oesophageal mucosa: clinical, pathological and epidemiological relevance in children: a cohort study 
BMJ Open  2012;2(1):e000493.
Eosinophilic oesophagitis (EO) shows eosinophilic infiltration of the mucosa and can present with symptoms indistinguishable from gastrooesophageal reflux disease (GORD). The authors describe the clinical, endoscopic and histopathological features of all cases of histological EO presenting during 2007–2008 with a 2-year follow-up. The incidence of paediatric EO and the features of a subgroup with features of both GORD and EO (‘overlap’ syndrome (OS)) are described.
Biopsies with an average of 15 eosinophils/high-power field (HPF) were reviewed in the cohort. OS was suggested when there was coexistence of clinical and histological features of EO and GORD (abnormal pH study), which improved with proton pump inhibitors.
Tertiary care.
All cases with ≥15 eosinophils/HPF entered the study.
Primary outcome measures
Patients with EO had an average of 15 eosinophils/HPF.
Secondary outcome measures
Other histological features of EO included microabscesses, dilated intercellular spaces, basal cell hyperplasia, papillary elongation, etc.
24 cases of EO were identified, 13 men and 11 women. The incidence of paediatric oesophageal eosinophilia in the region was 9/100 000 children. 11 of the 24 patients (46%) presented with some form of allergy, six with poor feeding/food aversion, five with dysphagia and four with vomiting. After follow-up, 56.5% were confirmed to have EO, 30.5% responded to treatment for GORD and were categorised as OS, 9% developed eosinophilic gastroenteritis and 4% did not have further upper gastrointestinal symptoms.
Accurate diagnosis of EO, especially the differentiation from GORD, requires appropriate clinicopathological correlation. A significant proportion of patients with eosinophilia in the mucosa also have GORD (OS). These patients improve after treating the underlying GORD. The study was registered as a Service Evaluation with the Trust (number SE74).
Article summary
Article focus
To estimate the incidence of oesophageal eosinophilia in the paediatric population of our region.
To describe the clinical presentation and the endoscopic appearances at presentation.
To appraise the natural history after 2-year follow-up and to recognise the clinical features of those cases that showed an overlap with gastrooesophageal reflux.
Key messages
During follow-up, 56.5% cases had eosinophilic oesophagitis confirmed, 9% improved with proton pump inhibitor treatment (overlap syndrome), 9% developed eosinophilic gastroenteritis and in 4% symptoms did not recur.
In 3 of the 13 patients with abnormal pH study (23%), the failure of proton pump inhibitor treatment and the improvement with oral steroids and/or diet modification, placed them in the category of eosinophilic oesophagitis.
The incidence of eosinophilia in the oesophagus in our region is 9/100 000 children, while that of eosinophilic oesophagitis is 4.5/100 000 children.
Strengths and limitations of this study
Defines the epidemiological features of oesophageal eosinophilia in the paediatric population in our region.
Highlights the importance of keeping longitudinal data on these patients.
The retrospective nature prevented a uniform clinical approach.
The small number of patients that underwent full evaluation for gastrooesophageal reflux disease weakens the conclusions on overlap syndrome.
PMCID: PMC3278487  PMID: 22240650
13.  Eosinophilic gastroenteritis in a young girl – long term remission under Montelukast 
BMC Gastroenterology  2005;5:24.
Eosinophilic gastrointestinal disorders are an emerging disease entity characterized by eosinophilic infiltration of the intestinal wall. Oral steroids can be still considered as first line treatment. Unfortunately relapses are quite common. Usually long term low-dose prednisone or immunosuppressive therapy is required, which is especially problematic in young patients. Thus a reliable steroid sparing agent with low side effects suitable for long term use is needed. There are strong hints to a similar pathophysiology of eosinophilic gastrointestinal disorders to that of asthma. Indeed leukotriene D4 plays an important role in the recruitment of eosinophils into the intestinal tissue causing damage. This patho-mechanism provides the rationale for the treatment with a leukotriene D4 receptor antagonist. Recently there have been first reports about successful short term use of Montelukast in eosinophilic gastrointestinal disorders.
Case presentation
We report the case of a 17 year old girl with a long history of severe abdominal complaints leading to several hospitalizations in the past. Mimicking the picture of an intestinal tuberculosis she received an anti mycobacterial treatment without any success. Marked eosinophilia in blood, ascites and tissue samples of the intestinal tract finally lead to the diagnosis eosinophilic gastroenteritis. Tapering off prednisone caused another severe episode of abdominal pain. At that point leukotriene antagonist Montelukast was started at a dose of 10 mg once daily. Steroids could be tapered off completely within six weeks. The patient has been free of symptoms for over two years by now. Routine examinations, blood tests and endoscopy have rendered regular results. So far no side effects were noted.
Here report about successful long term remission of eosinophilic gastroenteritis under Montelukast. Further randomized control trials are required to asses the full benefits of Montelukast therapy in the whole spectrum of eosinophilic gastrointestinal disorders.
PMCID: PMC1187886  PMID: 16026609
14.  Unusual presentations of eosinophilic gastroenteritis: Case series and review of literature 
Eosinophilic gastroenteritis (EG) is an uncommon disease characterized by focal or diffuse eosinophilic infiltration of the gastrointestinal tract, and is usually associated with dyspepsia, diarrhea and peripheral eosinophilia. Diffuse gastrointestinal tract and colonic involvement are uncommon. The endoscopic appearance may vary from normal to mucosal nodularity and ulceration. Gastrointestinal obstruction is unusual and is associated with predominantly muscular disease. We present five unusual cases of EG associated with gastric outlet and duodenal obstruction. Two cases presented with acute pancreatitis and one had a history of pancreatitis. Four cases responded well to medical therapy and one had recurrent gastric outlet obstruction that required surgery. Four out of the five cases had endoscopic and histological evidence of esophagitis and two had colitis. Two patients had ascites. These cases reaffirm that EG is a disorder with protean manifestations and may involve the entire gastrointestinal tract. Gastric outlet and/or small bowel obstruction is an important though uncommon presentation of EG. It may also present as esophagitis, gastritis with polypoid lesions, ulcers or erosions, colitis and pancreatitis and may mimic malignancy.
PMCID: PMC2678588  PMID: 19418590
Gastroenteritis; Eosinophilic; Gastrointestinal obstruction; Eosinophilic esophagitis; Eosinophilic colitis; Eosinophilic pancreatitis
15.  Microscopic colitis 
Microscopic colitis may be defined as a clinical syndrome, of unknown etiology, consisting of chronic watery diarrhea, with no alterations in the large bowel at the endoscopic and radiologic evaluation. Therefore, a definitive diagnosis is only possible by histological analysis. The epidemiological impact of this disease has become increasingly clear in the last years, with most data coming from Western countries. Microscopic colitis includes two histological subtypes [collagenous colitis (CC) and lymphocytic colitis (LC)] with no differences in clinical presentation and management. Collagenous colitis is characterized by a thickening of the subepithelial collagen layer that is absent in LC. The main feature of LC is an increase of the density of intra-epithelial lymphocytes in the surface epithelium. A number of pathogenetic theories have been proposed over the years, involving the role of luminal agents, autoimmunity, eosinophils, genetics (human leukocyte antigen), biliary acids, infections, alterations of pericryptal fibroblasts, and drug intake; drugs like ticlopidine, carbamazepine or ranitidine are especially associated with the development of LC, while CC is more frequently linked to cimetidine, non-steroidal antiinflammatory drugs and lansoprazole. Microscopic colitis typically presents as chronic or intermittent watery diarrhea, that may be accompanied by symptoms such as abdominal pain, weight loss and incontinence. Recent evidence has added new pharmacological options for the treatment of microscopic colitis: the role of steroidal therapy, especially oral budesonide, has gained relevance, as well as immunosuppressive agents such as azathioprine and 6-mercaptopurine. The use of anti-tumor necrosis factor-α agents, infliximab and adalimumab, constitutes a new, interesting tool for the treatment of microscopic colitis, but larger, adequately designed studies are needed to confirm existing data.
PMCID: PMC3501768  PMID: 23180940
Microscopic colitis; Lymphocytic colitis; Collagenous colitis; Watery diarrhea; Immunosuppressive agents; Anti-tumor necrosis factor-α agents
16.  Therapeutic comparison of a new budesonide/formoterol pMDI with budesonide pMDI and budesonide/formoterol DPI in asthma 
Budesonide/formoterol is an effective treatment for both asthma and chronic obstructive pulmonary disease. This study compared the efficacy and safety of a novel hydrofluoroalkane (HFA) pressurised metered-dose inhaler (pMDI) formulation of budesonide/formoterol with that of budesonide pMDI and budesonide/formoterol dry-powder inhaler (DPI; Turbuhaler®).
This was a 12-week, multinational, randomised, double-blind, double-dummy study involving patients aged ≥ 12 years with asthma. All patients had a forced expiratory volume in 1 s of 50–90% predicted normal and were inadequately controlled on inhaled corticosteroids (500–1600 mu g/day) alone. Following a 2-week run-in, during which they received their usual medication, patients were randomised (two inhalations twice daily) to budesonide pMDI 200 mu g, budesonide/formoterol DPI 160/4.5 mu g or budesonide/formoterol pMDI 160/4.5 mu g. The primary efficacy end-point was change from baseline in morning peak expiratory flow (PEF).
In total, 680 patients were randomised, of whom 668 were included in the primary analysis. Therapeutically equivalent increases in morning PEF were observed with budesonide/formoterol pMDI (29.3 l/min) and budesonide/formoterol DPI (32.0 l/min) (95% confidence interval: −10.4 to 4.9; p = 0.48). The increase in morning PEF with budesonide/formoterol pMDI was significantly higher than with budesonide pMDI (+28.7 l/min; p < 0.001). Similar improvements with budesonide/formoterol pMDI vs. budesonide pMDI were seen for all secondary efficacy end-points. Both combination treatments were similarly well tolerated.
Budesonide/formoterol, administered via the HFA pMDI or DPI, is an effective and well-tolerated treatment for adult and adolescent patients with asthma, with both devices being therapeutically equivalent.
PMCID: PMC2228375  PMID: 17887990
17.  Effect of budesonide/formoterol maintenance and reliever therapy on asthma exacerbations 
This randomised, double-blind, 6-month study compared budesonide/formoterol for maintenance and relief with salmeterol/fluticasone and a fixed maintenance dose of budesonide/formoterol, both with terbutaline for relief. Following a 2-week run-in, 3335 symptomatic adults and adolescents (mean FEV1 73% predicted, mean inhaled corticosteroid dose 745 μg/day) received budesonide/formoterol 160/4.5 μg one inhalation bid plus additional inhalations as needed, salmeterol/fluticasone 25/125 μg two inhalations bid plus as-needed terbutaline or budesonide/formoterol 320/9 μg one inhalation bid plus as-needed terbutaline. Budesonide/formoterol for maintenance and relief prolonged the time to first severe exacerbation requiring hospitalisation, emergency room treatment or oral steroids (primary variable) vs. fixed-dose salmeterol/fluticasone and budesonide/formoterol (p = 0.0034 and p = 0.023 respectively; log-rank test). Exacerbation rates were 19, 16 and 12 events/100 patients/6 months for salmeterol/fluticasone, fixed-dose budesonide/formoterol and budesonide/formoterol for maintenance and relief, respectively, [rate reduction vs. fixed-dose salmeterol/fluticasone (0.61; 95% CI 0.49–0.76, p < 0.001) and vs. fixed-dose budesonide/formoterol (0.72; 95% CI 0.57–0.90, p = 0.0048)]. Budesonide/formoterol maintenance and relief patients used less inhaled corticosteroid vs. salmeterol/fluticasone and fixed-dose budesonide/formoterol patients. All treatments provided similar marked improvements in lung function, asthma control days and asthma-related quality of life. Budesonide/formoterol for maintenance and relief reduces asthma exacerbations and maintains similar daily asthma control at a lower overall drug load compared with fixed-dose salmeterol/fluticasone and budesonide/formoterol.
PMCID: PMC1920547  PMID: 17362472
18.  Randomised, double-blind, placebo-controlled trial of oral budesonide for prophylaxis of acute intestinal graft-versus-host disease after allogeneic stem cell transplantation (PROGAST) 
BMC Gastroenterology  2014;14(1):197.
Gastrointestinal graft–versus-host disease (GvHD) is a potentially life-threatening complication after allogeneic stem cell transplantation (SCT). Since therapeutic options are still limited, a prophylactic approach seems to be warranted.
In this randomised, double-blind-phase III trial, we evaluated the efficacy of budesonide in the prophylaxis of acute intestinal GvHD after SCT. The trial was registered at, number NCT00180089.
Patients were randomly assigned to receive either 3 mg capsule three times daily oral budesonide or placebo. Budesonide was applied as a capsule with pH-modified release in the terminal ileum. Study medication was administered through day 56, follow-up continued until 12 months after transplantation. If any clinical signs of acute intestinal GvHD appeared, an ileocolonoscopy with biopsy specimens was performed.
The crude incidence of histological or clinical stage 3–4 acute intestinal GvHD until day 100 observed in 91 (n =48 budesonide, n =43 placebo) evaluable patients was 12.5% (95% CI 3-22%) under treatment with budesonide and 14% (95% CI 4-25%) under placebo (p = 0.888). Histologic and clinical stage 3–4 intestinal GvHD after 12 months occurred in 17% (95% CI 6-28%) of patients in the budesonide group and 19% (CI 7-32%) in the placebo group (p = 0.853). Although budesonide was tolerated well, we observed a trend towards a higher rate of infectious complications in the study group (47.9% versus 30.2%, p = 0.085). The cumulative incidences at 12 months of intestinal GvHD stage >2 with death as a competing event (budesonide 20.8% vs. placebo 32.6%, p = 0.250) and the cumulative incidence of relapse (budesonide 20.8% vs. placebo 16.3%, p = 0.547) and non-relapse mortality (budesonide 28% (95% CI 15-41%) vs. placebo 30% (95% CI 15-44%), showed no significant difference within the two groups (p = 0.911). The trial closed after 94 patients were enrolled because of slow accrual. Within the limits of the final sample size, we were unable to show any benefit for the addition of budesonide to standard GvHD prophylaxis.
Budesonide did not decrease the occurrence of intestinal GvHD in this trial. These results imply most likely that prophylactic administration of budenoside with pH-modified release in the terminal ileum is not effective.
PMCID: PMC4258813  PMID: 25425214
Acute intestinal Graft-versus-host disease; Prophylaxis; Allogeneic stem cell transplantation; Budesonide
19.  Oral Ondansetron Administration in Emergency Departments to Children with Gastroenteritis: An Economic Analysis 
PLoS Medicine  2010;7(10):e1000350.
Stephen Freedman and colleagues performed a cost analysis of the routine administration of ondansetron in both the United States and Canada and show that its routine administration to eligible children in such settings could provide substantial benefit.
The use of antiemetics for children with vomiting is one of the most controversial decisions in the treatment of gastroenteritis in developed countries. Ondansetron, a selective serotonin receptor antagonist, has been found to be effective in improving the success of oral rehydration therapy. However, North American and European clinical practice guidelines continue to recommend against its use, stating that evidence of cost savings would be required to support ondansetron administration. Thus, an economic analysis of the emergency department administration of ondansetron was conducted. The primary objective was to conduct a cost analysis of the routine administration of ondansetron in both the United States and Canada.
Methods and Findings
A cost analysis evaluated oral ondansetron administration to children presenting to emergency departments with vomiting and dehydration secondary to gastroenteritis from a societal and health care payer's perspective in both the US and Canada. A decision tree was developed that incorporated the frequency of vomiting, intravenous insertion, hospitalization, and emergency department revisits. Estimates of the monetary costs associated with ondansetron use, intravenous rehydration, and hospitalization were derived from administrative databases or emergency department use. The economic burden in children administered ondansetron plus oral rehydration therapy was compared to those not administered ondansetron employing deterministic and probabilistic simulations. We estimated the costs or savings to society and health care payers associated with the routine administration of ondansetron. Sensitivity analyses considered variations in costs, treatment effects, and exchange rates. In the US the administration of ondansetron to eligible children would prevent approximately 29,246 intravenous insertions and 7,220 hospitalizations annually. At the current average wholesale price, its routine administration to eligible children would annually save society US$65.6 million (US$49.1–US$81.1) and health care payers US$61.1 million (US$46.2–US$76.3). In Canada the administration of ondansetron to eligible children would prevent 4,065 intravenous insertions and 1,003 hospitalizations annually. Its routine administration would annually save society CDN$1.72 million (CDN$1.15–CDN$1.89) and the health care system CDN$1.18 million (CDN$0.88–CDN$1.41).
In countries where intravenous rehydration is often employed, the emergency department administration of oral ondansetron to children with dehydration and vomiting secondary to gastroenteritis results in significant monetary savings compared to a no-ondansetron policy.
Please see later in the article for the Editors' Summary
Editors' Summary
Although many episodes of gastroenteritis in children are mild and can be managed with oral fluids, including oral rehydration therapy (ORT), some cases are severe enough to require hospital admission for intravenous fluids. Administration of an antiemetic (a drug that reduces nausea and sickness) can be clinically effective, especially ondansetron, (a drug that belongs to a class of drugs known as selective serotonin receptor antagonists), which is safer than other antiemetics, such as promethazine and prochlorperazine, and in which there is good evidence to support its effectiveness in improving the success of ORT in children with gastroenteritis. Furthermore, studies have shown that administration of ondansetron decreases the risk of further vomiting, and hence the need for intravenous rehydration, and immediate hospital admission. However, despite the proven clinical benefits of ondansetron, clinical practice guidelines continue to recommend against the use of antiemetics in gastroenteritis because the evidence of cost savings is not yet clear. Last year, the UK's National Institute for Health and Clinical Excellence recommended that such a cost analysis should be a key research priority in pediatric gastroenteritis.
Why Was This Study Done?
This study—which is an economic analysis—was conducted in response to the various calls for the need to demonstrate the cost effectiveness of ondansetron in the management of pediatric gastroenteritis.
What Did the Researchers Do and Find?
The researchers analysed the costs of the administration of oral ondansetron in both the US and Canada, if routinely given to children with gastroenteritis-induced vomiting and dehydration in the emergency department setting. In addition, the researchers calculated the incremental cost of ondansetron per quality-adjusted life-year (QALY) gained from a health care perspective, compared to a regimen without ondansetron administration. The authors conducted a particular type of statistical analysis, known as decision tree analysis, to compare the two treatment options—administering ondansetron and not administering ondansetron in addition to ORT, with the clinical outcomes (further vomiting, intravenous rehydration, and hospitalization) determined on the basis of the documented efficacy of ondansetron. In addition, the researchers conducted their analyses from both the societal perspective (which included all costs, both direct—the resources required to produce a service; and indirect—productivity costs) and the health care payer's perspective. The US and Canada use similar medical resources, management programs, and treatment guidelines, but as prices differ dramatically (for example, the cost of hospitalization in the US is 8-fold higher than that in Canada), the researchers conducted a separate analysis for each country.
On the basis of data from the US, the researchers found that the administration of ondansetron to eligible children would prevent approximately 29,246 intravenous insertions and 7,220 hospitalizations every year with an annual saving of US$65.6 million to society and US$61.1 million to payers of health care costs if this drug was given routinely. When using Canadian data, the researchers found that the administration of ondansetron to eligible children would prevent 4,065 intravenous insertions and 1,003 hospitalizations every year, with an annual saving of CDN$1.72 million to society and CDN$1.18 million to payers of health care costs if this drug was given routinely.
What Do These Findings Mean?
The results of this study show that the emergency department administration of oral ondansetron to children with dehydration and vomiting secondary to gastroenteritis results in significant monetary savings from both societal and health care perspectives compared to a policy that does not include ondansetron administration. Furthermore, the societal savings are probably an underestimate because in their model, the researchers assumed that only 10% of children with gastroenteritis presenting to an emergency department would meet eligibility criteria (in reality, this proportion would likely be higher). In addition, the researchers did not include estimates for ondansetron administration in the clinic or private office setting, as although such use is common, no estimates of eligibility and efficacy were available.
Therefore, in addition to being clinically beneficial, the administration of oral ondansetron to children with dehydration and vomiting secondary to gastroenteritis is also economically advantageous.
Additional Information
Please access these Web sites via the online version of this summary at
Patient UK and the US National Institutes of Health provide information for patients on ondansetron
Patient UK provides information on gastroenteritis in children
BBC Health also provides general information on gastroenteritis
The Centers for Disease Control and Prevention contains a report on managing acute gastroenteritis among children
PMCID: PMC2953527  PMID: 20967234
20.  In Vitro Effects of Budesonide on Eosinophil-Basophil Lineage Commitment 
IL-5 is the primary cytokine that stimulates the production and survival of eosinophils and basophils from progenitor cells. The inhaled glucocorticoid, budesonide, has been shown to exert a therapeutic effect via suppression of eosinophil/basophil progenitors in vivo. Since various steroids have exhibited the ability to enhance eosinophil/basophil progenitor differentiation, we examined the effects of budesonide in vitro. Bone marrow and cord blood samples were obtained and cultured in the presence of IL-5 alone or IL-5 plus budesonide. Eosinophil/basophil colony-forming units were enumerated from cultured nonadherent mononuclear cells and from purified CD34+ cells. CD34+ cells with and without budesonide were also examined for up-regulation of ERK1/2, MAPK and GATA-1 using real time-PCR. Results: i) up-regulation of eosinophil/basophil colony-forming units is due to the direct effects of budesonide on IL-5-stimulated progenitors; ii) GATA-1 is likely involved in the early amplification of eosinophil/basophil progenitor commitment leading to increased differentiation. A potential transcriptional pathway has been identified which may mediate the effects of budesonide on eosinophil/basophil lineage commitment.
PMCID: PMC2606647  PMID: 19343093
Budesonide; eosinophil/basophil progenitors; corticosteroids; GATA-1; IL-5.
21.  Daily versus as-needed inhaled corticosteroid for mild persistent asthma (The Helsinki early intervention childhood asthma study) 
Archives of Disease in Childhood  2007;93(8):654-659.
To compare the effect of inhaled budesonide given daily or as-needed on mild persistent childhood asthma.
Patients, design and interventions:
176 children aged 5–10 years with newly detected asthma were randomly assigned to three treatment groups: (1) continuous budesonide (400 μg twice daily for 1 month, 200 μg twice daily for months 2–6, 100 μg twice daily for months 7–18); (2) budesonide, identical treatment to group 1 during months 1–6, then budesonide for exacerbations as needed for months 7–18; and (3) disodium cromoglycate (DSCG) 10 mg three times daily for months 1–18. Exacerbations were treated with budesonide 400 μg twice daily for 2 weeks.
Main outcome measures:
Lung function, the number of exacerbations and growth.
Compared with DSCG the initial regular budesonide treatment resulted in a significantly improved lung function, fewer exacerbations and a small but significant decline in growth velocity. After 18 months, however, the lung function improvements did not differ between the groups. During months 7–18, patients receiving continuous budesonide treatment had significantly fewer exacerbations (mean 0.97), compared with 1.69 in group 2 and 1.58 in group 3. The number of asthma-free days did not differ between regular and intermittent budesonide treatment. Growth velocity was normalised during continuous low-dose budesonide and budesonide therapy given as needed. The latter was associated with catch-up growth.
Regular use of budesonide afforded better asthma control but had a more systemic effect than did use of budesonide as needed. The dose of ICS could be reduced as soon as asthma is controlled. Some children do not seem to need continuous ICS treatment.
PMCID: PMC2532957  PMID: 17634183
22.  Longstanding eosinophilic gastroenteritis of more than 20 years 
Eosinophilic gastroenteritis (EGE) is an eosinophil-predominant inflammatory process that may be detected in endoscopic gastric or intestinal biopsies. The long-term natural history and effects of EGE treatment are not known. A 44-year-old man with abdominal pain was treated with oral ketotifen and followed for more than 20 years. Ketotifen provided symptomatic benefit, with prompt clinical relapse if the drug was discontinued. However, despite the use of ketotifen, the endoscopic abnormalities persisted and appeared to progress. Gastric body and antral mucosal folds appeared thickened, erythematous and friable, with minimal erosive change. Later, even during long asymptomatic periods suggesting clinical ‘remission’, inflammatory polypoid change, previously described in children with EGE, developed with mucosal ‘pock-marking’ and apparent scarring. Ketotifen treatment does not appear to prohibit or reverse the inflammatory process in the gastric mucosa in EGE, although long-term effects of steroids may be avoided. In the future, treatment of EGE may involve monoclonal antibody agents that target the specific biological effects of the eosino-phil, apparently central to this unusual inflammatory process.
PMCID: PMC2776554  PMID: 19816628
Eosinophilic gastroenteritis; Eosinophils; Gastric polyps; Ketotifen; Mast cells
23.  Acute Eosinophilic Ascites in a Middle-Aged Man 
Eosinophilic gastroenteritis is a rare condition characterized by recurrent eosinophilic infiltration of portions of the GI tract and presenting with nonspecific GI symptoms in association with peripheral eosinophilia. Its etiology and pathogenesis remain unclear and its symptoms overlap with many GI and systemic diseases. Thus, both gastroenterologists and general internists need to be aware of this rare condition. We present a case of a 55-year-old male with diffuse abdominal pain and distention for two weeks. His physical examination was significant for moderate ascites. Initial work-up demonstrated severe peripheral blood eosinophilia, normal liver function tests, thickening of the stomach and small bowel wall, and elevated serum IgE. Upper endoscopy and extensive testing for malignancy and parasitic infections failed to establish a diagnosis. Ascitic fluid analysis showed significant eosinophilia. Further, a full-thickness jejunal showed marked eosinophilic infiltration of the serosa and muscularis propria. Subsequent treatment with oral prednisone resulted in normalization of laboratory and radiologic abnormalities in a few week period.
PMCID: PMC3356866  PMID: 22649743
24.  Formulation and evaluation of sustained release enteric-coated pellets of budesonide for intestinal delivery 
The aim of present work was to develop intestinal-targeted pellets of Budesonide, a potent glucocorticoid, used for the treatment of ulcerative colitis and Crohn's disease by extrusion and spheronization method. Current available oral formulations of Budesonide have low efficacy because of the premature drug release in the upper part of the gastrointestinal tract. In this study, a pH-controlled intestinal-targeted pellet of budesonide was established using 32 full factorial design by giving an enteric coating with Eudragit S100.
Materials and Methods:
Budesonide-sustained release pellets were prepared by extruder and spheronization technique using a combination of water-soluble and permeable polymers by applying 32 full factorial design. The pellets were coated by spray coating technique using Eudragit S100 as an enteric polymer. The pellets were characterized for its flowability, sphericity, friability, and in vitro drug release. Release behaviour was studied in different pH media. The release profile was studied for the mechanism of drug release.
The optimized formulation showed negligible drug release in the stomach followed by release for 12 h in the intestinal pH. Differential scanning calorimetry and Fourier Transform Infrared Spectroscopy studies indicated no interaction between drug and polymer. Scanning Electron Microscopy image of coated pellets suggested a uniform and smooth coat over the surface of pellets. Accelerated stability studies showed a stable nature of drug in the formulation. All evaluation parameter showed that pellets were good in spherocity and flowability.
Sustained release pellets of Budesonide could be prepared by extrusion and spheronization which released the drug in intestinal pH for an intestine to treat inflammatory bowel disease. A ratio of polymer combination could be decided using a full factorial design.
PMCID: PMC3853760  PMID: 24350040
Budesonide; eudragit S100; extruder spheronizer; inflammatory bowel disease; spray coating; sustained release
25.  Regular treatment with formoterol and an inhaled corticosteroid versus regular treatment with salmeterol and an inhaled corticosteroid for chronic asthma: serious adverse events 
An increase in serious adverse events with the use of both regular formoterol and regular salmeterol (long-acting beta2-agonists) in chronic asthma has been demonstrated in comparison with placebo in previous Cochrane reviews. This increase was significant in trials that did not randomise participants to an inhaled corticosteroid. However, systematic reviews of trials in which each drug was randomised with an inhaled corticosteroid did not demonstrate significant increases in serious adverse events. The confidence intervals were found to be too wide to be sure that the addition of an inhaled corticosteroid renders regular long-acting beta2-agonists completely safe; there were fewer participants and insufficient serious adverse events in these trials to come to a definitive decision about the safety of combination treatments.
We set out to compare the risks of mortality and non-fatal serious adverse events in trials which have randomised patients with chronic asthma to regular formoterol versus regular salmeterol, when each are used with an inhaled corticosteroid as part of the randomised treatment.
Search methods
We identified trials using the Cochrane Airways Group Specialised Register of trials. We checked manufacturers’ websites of clinical trial registers for unpublished trial data and also checked Food and Drug Administration (FDA) submissions in relation to formoterol and salmeterol. The date of the most recent search was August 2011.
Selection criteria
We included controlled clinical trials with a parallel design, recruiting patients of any age and severity of asthma, if they randomised patients to treatment with regular formoterol versus regular salmeterol (each with a randomised inhaled corticosteroid) and were of at least 12 weeks duration.
Data collection and analysis
Two review authors independently selected trials for inclusion in the review and extracted outcome data. We sought unpublished data on mortality and serious adverse events from the sponsors and authors.
Main results
Ten studies on 6769 adults and adolescents met the eligibility criteria of the review. Seven studies (involving 5935 adults and adolescents) compared formoterol and budesonide to salmeterol and fluticasone. All but one study administered the products as a combined inhaler, and most used formoterol 12 μg and budesonide 400 μg twice daily versus salmeterol 50 μg and fluticasone 250 μg twice daily. There were two deaths overall (one on each combination) and neither were thought to be related to asthma.
There was no significant difference between treatment groups (formoterol/budesonide versus salmeterol/fluticasone) for non-fatal serious adverse events, either all-cause (Peto odds ratio (OR) 1.14; 95% confidence interval (CI) 0.82 to 1.59, I2 = 26%) or asthma-related (Peto OR 0.69; 95% CI 0.37 to 1.26, I2 = 33%). Over 23 weeks the rates for all-cause serious adverse events were 2.6% on formoterol and budesonide and 2.3% on salmeterol and fluticasone, and for asthma-related serious adverse events, 0.6% and 0.8% respectively.
There was one study (228 adults) comparing formoterol and beclomethasone to salmeterol and fluticasone, but there were no deaths or hospital admissions. One study (404 adults) compared formoterol and mometasone to salmeterol and fluticasone for 52 weeks, but the small number of events leaves considerable uncertainty about the comparative safety of the two products. Similarly one study (202 adults) compared formoterol and fluticasone with salmeterol and fluticasone, but there was only one serious adverse event in each group.
No studies were found in children.
Authors’ conclusions
The seven identified studies in adults did not show any significant difference in safety between formoterol and budesonide in comparison with salmeterol and fluticasone. Asthma-related serious adverse events were rare, and there were no reported asthma-related deaths. There was a single, small study comparing formoterol and beclomethasone to salmeterol and fluticasone in adults, a single study comparing formoterol and mometasone with salmeterol and fluticasone in adults, and a single study comparing formoterol and fluticasone with salmeterol and fluticasone in adults.
No studies were found in children, so no conclusion can be drawn for this age group.
Overall there is insufficient evidence to decide whether regular formoterol in combination with budesonide, beclometasone, fluticasone or mometasone have equivalent or different safety profiles from salmeterol in combination with fluticasone.
PMCID: PMC4015852  PMID: 20091646
Administration, Inhalation; Albuterol [administration & dosage; adverse effects; *analogs & derivatives]; Androstadienes [administration & dosage; adverse effects]; Anti-Asthmatic Agents [administration & dosage; *adverse effects]; Asthma [*drug therapy; mortality]; Budesonide [administration & dosage; adverse effects]; Drug Therapy, Combination [adverse effects]; Ethanolamines [administration & dosage; *adverse effects]; Glucocorticoids [administration & dosage; *adverse effects]; Randomized Controlled Trials as Topic; Adolescent; Adult; Humans

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